The present invention relates to processes for the preparation of cyclic polypeptides, such as, for example, cyclic undecapeptides, such as alisporivir.
Alisporivir is a cyclophilin (Cyp) inhibitor used for the treatment of hepatitis C virus (HCV) infection or HCV induced disorders as described in WO 2006/038088. Furthermore, WO2009/042892 describes methods for the use of alisporivir in the treatment of multiple sclerosis; WO2009/098577 describes methods for the use of alisporivir in the treatment of muscular dystrophy; WO2008/084368 describes methods for the use of alisporivir in the treatment of Ullrich congenital muscular dystrophy.
Alisporivir and a synthesis thereof are described in WO 00/01715. Alisporivir has been attributed the CAS Registry Number 254435-95-5.
Processes for the preparation of Alisporivir on laboratory scale are described by J. F. Guichoux in “De nouveaux analogues de Cycloposrine A comme agent anti-HIV-1” PhD thesis, Faculte des Sciences de L'Universite de Lausanne, 2002, in WO2006/038088, and in WO2008/084368.
Cyclic undecapeptides, as represented below, are cyclic polypeptides of Formula (Ia), wherein n=2.
Alisporivir (Formula I) is a cyclic undecapeptide of Formula (Ib) wherein n=2, aa1 is D-MeAla and aa2 is EtVal.

Generic Formula:
Cyclo-(AXX1-AXX2-AXX3-AXX4-AXX5-AXX6-AXX-7-AXX8-AXX9-AXX10-AXX11), should cover examples from case WO2010/052559 A1 as fragmentation made at key Sar fragment    AXX1=MeBmt, Bmt, MeLeu, Desoxy-MeBmt, Methylaminooctanoic acid    AXXn 2=Abu, Ala, Thr, Val, Nva    AXX3=Sar    AXX4=MeLeu, Val    AXX5=Val, Nva    AXX6=MeLeu, Leu    AXX7=Ala, Abu    AXX8=D-Ala    AXX9=MeLeu, Leu    AXX10=MeLeu, Leu    AXX11=MeVal, Val, D-MeVal
And all other combinations covered in WO 2010/052559 A1
Over the last several years, cyclosporin A (CyA) has been used as a raw material for a variety of synthetic cyclic undecapeptides which are useful for the treatment of inflammatory or viral diseases. Cyclic undecapeptides may be obtained bystrain selection, however obtaining most un-natural derivatives requires a chemical transformation which relies on opening of the cyclic polypeptide, for example, of Formula (Ia) or of Formula (Ib) and subsequent amino acid replacement.
Traditionally, cyclic polypeptide, for example of Formula (Ia) are opened in a highly selective process and an amino acid residue is removed via the Edman degradation to access the opened cyclic polypeptide as a key intermediate (Wenger, R. M. In Peptides 1996; Ramage, R.; Epton, R., Eds.; The European Peptides Society, 1996; pp. 173; Wenger, R. M. et al. Tetrahedron Letters 2000, 41, 7193.). Numerous scientists and companies have used this reliable and selective strategy wherein pure cyclosporin A and purification by column chromatography have been used to obtain cyclic undecapeptides.
Furthermore, purification of products, such as opened cyclosporin A, involve several steps of purification by liquid chromatography on silica. Beside the moderate overall obtained yield, the major drawback of this purification scheme is the very high costs for the chromatography steps. Large-scale purification processes of such products derived from cyclosporin A or its structural analogues described in the literature generally involve a chromatographic purification or at least a pre-purification by adsorption chromatography. Such pre-purification may be followed, for instance, by extraction, counterflow extraction, and/or supercritical fluid extraction.
However, none of these techniques appear to be fully satisfactory for obtaining the key opened intermediates with the desired quality requirements, with an acceptable overall yield, and at an acceptable cost for an industrial scale production, as costly precursors of high quality were required.
We identified that dimethoxycarbenium ions (described in Novartis patent application EP 0 908 461 A1 for the methylation of Cephalosporine derivatives), do the same chemistry as oxonium ions (trimethyl or triethyloxonium Meerwein salts) in the opening of the macrocyclic polypeptide. The new conditions can advantageously be prepared in situ, thus avoiding the handling of hazardous and hygroscopic substance, can proceed in a variety of solvents such as for example toluene, xylene, anisole, by-passing the need for using the undesirable chlorinated solvents such as dichloromethane or dichloroethane, and avoid the use of oxonium Meerwein salts originating from the genotoxic epichlorhydrin. Either the dedicated carbenium tetrafluoroborate salt or the in situ generated reactive species made by the reaction of boron trifluoride and an orthoester derivative, preferably trimethyl orthoformate, will result in the desired opened polypeptides such as compound 3 below.
We identified an improved process which maintains the advantage of a highly selective Edman degradation strategy while taking full advantage of newly identified crystalline intermediates.
The following disclosure presents newly isolated and crystalline intermediates derived from the
and a process to generate and purify them, via methods such as crystallizations. This approach allows for a rapid, practical and much more effective access to opened cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G and can be used to produce cyclic undecapeptides, such as alisporivir. Furthermore, the process according to the present disclosure may also be applied to other cyclosporins that can be opened via the same sequence. It was found that opened cyclosporin salts, such as hydrochloric acid (HCl), fluoroboric acid (HBF4), or hexafluorophosphoric acid (HPF6), can be formed at several stages.
The present invention provides novel crystalline intermediates, such as cylosporine esters, such as acetate, pivaloate, and opened cyclosporin A, cyclosporin B, cyclosporin D or cyclosporin G salts such as the HCl salt, the HBF4 salt, or the HPF6 salt, and processes to generate them.